title: Altered 2-thiouridylation impairs mitochondrial translation in reversible infantile respiratory chain deficiency.
abstract: Childhood-onset mitochondrial encephalomyopathies are severe, relentlessly progressive conditions. However, reversible infantile respiratory chain deficiency (RIRCD), due to a homoplasmic mt-tRNA(Glu) mutation, and reversible infantile hepatopathy, due to tRNA 5-methylaminomethyl-2-thiouridylate methyltransferase (TRMU) deficiency, stand out by showing spontaneous recovery, and provide the key to treatments of potential broader relevance. Modification of mt-tRNA(Glu) is a possible functional link between these two conditions, since TRMU is responsible for 2-thiouridylation of mt-tRNA(Glu), mt-tRNA(Lys) and mt-tRNA(Gln). Here we show that down-regulation of TRMU in RIRCD impairs 2-thiouridylation and exacerbates the effect of the mt-tRNA(Glu) mutation by triggering a mitochondrial translation defect in vitro. Skeletal muscle of RIRCD patients in the symptomatic phase showed significantly reduced 2-thiouridylation. Supplementation with l-cysteine, which is required for optimal TRMU function, rescued respiratory chain enzyme activities in human cell lines of patients with RIRCD as well as deficient TRMU. Our results show that l-cysteine supplementation is a potential treatment for RIRCD and for TRMU deficiency, and is likely to have broader application for the growing group of intra-mitochondrial translation disorders.
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Central Parkway, Newcastle upon Tyne NE1 3BZ, UK.
authors.forename: Veronika
authors.initials: V
authors.lastname: Boczonadi
authors.forename: Paul M
authors.initials: PM
authors.lastname: Smith
authors.forename: Angela
authors.initials: A
authors.lastname: Pyle
authors.forename: Aurora
authors.initials: A
authors.lastname: Gomez-Duran
authors.forename: Ulrike
authors.initials: U
authors.lastname: Schara
authors.forename: Mar
authors.initials: M
authors.lastname: Tulinius
authors.forename: Patrick F
authors.initials: PF
authors.lastname: Chinnery
authors.forename: Rita
authors.initials: R
authors.lastname: Horvath
mesh_terms: D002460:Cell Line; D003545:Cysteine / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D008928:Mitochondria / Q000235:genetics*; D028361:Mitochondrial Diseases / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D017237:Mitochondrial Encephalomyopathies / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D024101:Mitochondrial Proteins / Q000235:genetics* / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism; D009154:Mutation; D032446:Myoblasts / Q000378:metabolism; D010085:Oxidative Phosphorylation; D014176:Protein Biosynthesis / Q000235:genetics* / Q000502:physiology; D012343:RNA, Transfer / Q000235:genetics / Q000378:metabolism*; D013891:Thiouridine / Q000031:analogs & derivatives / Q000378:metabolism; D012359:tRNA Methyltransferases / Q000235:genetics* / Q000378:metabolism
chemical_list: C105273:2-thiouridine; D024101:Mitochondrial Proteins; D013891:Thiouridine; D012343:RNA, Transfer; D012359:tRNA Methyltransferases; C496706:TRMU protein, human; D003545:Cysteine